Conventional nuclear cardiac imaging performed with either planar, single photon emission computed tomography (SPECT) or positron emission tomography (PET) camera and computer detection systems currently utilizes comparison of “rest” and “stress” imaging for comparisons to determine the presence or absence of ischemia and infarcted tissue. Acquisition of cardiac images using these cameras and nuclear isotopes under either stress or resting conditions are defined as nuclear cardiac studies (NCS).
By convention, patients may have either the “stress” study or “rest” study done first. When there is no abnormality seen on either study, the patient is reported to be “normal.” When the “stress” image is abnormal and the “rest” image is normal, the interpretation is that of ischemia. When both “stress” and “rest” images are abnormal (in the same region of the heart), the interpretation is no ischemia but infarction.
Currently, there are more than 11 million nuclear cardiac studies performed in the U.S. yearly with a 35% error rate. This error rate however does not take into account errors made where the area of the heart is incorrect (e.g. ischemia reported in the area of the right coronary artery with angiographic analysis showing it is the left anterior descending artery). These studies are considered correct “for detection of ischemia” even though the area of the heart involved is incorrect. Of the 35% known errors, approximately 70,000 to 90,000 individuals are told they do not have ischemic heart disease (MD) only to go home and die soon thereafter from IVD and myocardial infarction (MI).
The first nuclear cardiac studies (NCS) looking for coronary artery disease (CAD) were introduced in the 1970's and employed exercise stress to increase the demand for coronary blood flow and detect IHI) thought to be due to narrowing of one or more coronary arteries (Stenosis Flow Reserve/SFR© TX 7-451-241). Following the use of exercise or pharmacologic stress, Thallium-201 (T1-201) was injected through an intravenous catheter and one hour later “stress” images were taken followed three to four hours by the acquisition of “redistribution” images. The images “stress-redistribution” were then compared using the method described supra to make a determination of ischemia and/or infarction.
With the introduction of Technetium-99m hexakis 2-methoxyisobutylisonitrile (sestamibi) in the late 1980's, the pharmaceutical company owning sestamibi then and now, recommend that two separate injections of the isotope be given, one at “stress” and another at “rest.” This recommendation was based upon the premise that sestamibi did not redistribute like T1-201. These studies are plagued by the same 35% error rate noted supra.
In 2001 we noticed, while developing Breast Enhanced Scintigraphy Test (B.E.S.T.©) Imaging, that imaging of the heart performed five minutes (FIG. 1) after the injection of sestamibi following either physiologic stress using a pharmacologic agent or using exercise stress, showed a different result than images taken sixty minutes after the isotope was injected. Conventional thinking was that sestamibi did not redistribute and if it did Crane showed this occurred 28 minutes after injection; NOT earlier. However, the five-minute images demonstrated not only that sestamibi redistributes, but also that it is this initial “early” five-minute acquisition that was crucial to differentiating IVD. While Crane reported that sestamibi washout could occur after 28 minutes under ischemic conditions, there is no report indicating this could occur earlier or would be diagnostically useful. Crane shows no five minutes post injection characteristics indicating the usefulness of imaging at five-minutes and there is no report other than our work, which looks at the clinical importance of looking at the differences between five and sixty minute image analysis and it's ramifications on the detection of IVD. Specifically, Crane was not defining “redistribution”, only that the isotope left tissue earlier than expected; viz. at 28 minutes. The term “redistribution” (other than our work) of sestamibi employed in the literature to date talks about changes between “stress” and “rest” sestamibi images and NOT the phenomena we have noted between five and sixty-minute “stress” images.
Additionally, we noted prominent uptake of sestamibi by the thymus gland (see FIG. 1b), which is detectable only during the first ten-minutes following injection of the isotope following pharmacologic or physiologic stress. Images taken later than this ten-minute interval showed no significant detectability of the thymus gland. Results showed IVD and elevated markers of IVD, specifically hs-CRP associated with thymus uptake and detectability. Successful treatment of the IVD demonstrated an absence of thymus detectability using this method, a normalization of the hs-CRP level and improvement in subsequent IVD.
Since SFR© as we have defined it, is the difference between peak blood flow and least blood flow under physiologic demand, not implied to be resting flow, the detection of IVD requires a comparison of same state conditions for correct interpretation of diagnosis of IVD, including IHD and VIP disease. This same state condition is “stress”-“stress.”
Comparison of same state “stress”-“stress” image comparisons using five and sixty-minute images acquired by NCS can be visually (qualitatively) noted to be different in individuals with IVD. This is determined “quantitatively” by comparing identical regions of interest (ROIs) from the five-minute image(s) with the sixty-minutes image(s). When there is no IVD, the “quantified” counts per ROI are the same as that seen at sixty-minutes, correcting for isotope decay (appendix A). While this varies depending upon the isotope used and the actual time between the two sets of images, taken post-stress, a mathematical model (viz. FHRWW©) compares the “quantified” counts in the ROIs between the two sets of images (appendix A). When VIP is present by intravascular (IVUS) ultrasound and/or angiographic results, little impairment in coronary blood flow is seen within the lumen of the artery. Under these conditions, the major limitation is the ability of the artery to dilate and augment coronary flow to peak levels and a diminished SFR© is seen. These individuals take longer for the isotope to accumulate in that region of the heart compared with regions with normal blood flow. As a result, the initial five-minute counts are less than the later sixty-minute counts. This is defined as “wash-in” and reflects a significant number of individuals whose IVD is missed by “rest-stress” imaging where only a sixty-minute post stress image is obtained, when the isotope has had sufficient time to “wash-in.”
When IVD is associated with coronary lumen narrowing, the initial five-minute counts per ROI are greater than that present in the same ROI at sixty-minutes after correction for isotope decay (defined in appendix A). Under these conditions, “washout” of the isotope is seen, but in fact, this “washout” or loss of isotope above expected decay of the isotope, is associated with MD. Unlike the errors seen in “rest-stress” imaging, “stress-stress” FHRWW © correctly identifies the diseased artery, as confirmed by coronary angiography.
When IVD is absent and coronary blood flow is not impaired, comparison of identical ROIs from the five-minute and sixty-minute images, reveal similar isotope counts, corrected for isotope decay (appendix A). Given the information obtained from “wash-in” “washout” this represents a state where the isotope is constantly being delivered to myocytes, taken up by the cells, released from the cells, retaken up by the cells, repeating the process during isotope decay.
Multiple methods have been studied to determine if impaired myocyte function is the result of MI or whether there is stunned or hibernating myocardium present. Stunned or hibernating myocardium reflects damaged/injured cardiac tissue, which is not demonstrating contractile or other grossly detectable cellular function. However, under these conditions, the cells have been “temporarily” damaged and with sufficient recovery of blood flow, my return to normal function. Stunned myocardium represents a state where the effect is of less duration than that noted in hibernating myocardium. These other methods have not demonstrated clinical utility and most if not all of them have subsequently been abandoned.
Similarly, the detection of cardiac IVD, tissue viability requires a comparison of same state conditions; but under “rest”−“rest” conditions. “Rest”-“rest” compares myocyte ability to “redistribute” the isotope being imaged by the nuclear camera without the introduction of pharmacologic or physiologic stress.
As with “stress”-“stress” detection of IVD, the comparison of same state “rest” “rest” ROIs can be used to determine tissue viability (FHRWW©). When the five and sixty-minute counts for ROIs are compared, they yield cardiac tissue viability when compared with electrocardiogram, enzymatic and echocardiographic results. Here when the five and sixty-minute counts per ROI are essentially the same after correction for isotope decay, cardiac tissue is “normal” and functional.
When the cardiac tissue in infarcted, both the five-minute ROI counts are lower than the “normal” myocardium, with little if any change between the counts at five and sixty minutes. Stunned/hibernating myocardium initially has ROI counts greater than the infarcted tissue but less than the “normal” myocardium.
Efforts to improve “qualitative” image comparison have resulted in nuclear camera companies increasing the number of pixels for visual resolution. These results give a visually pleasing appearance; however, there is no published data as to the “quantitative” reliability of these images. Since FHRWW© “quantification” requires accurate statistical counts, we looked at the ability of different settings to produce different results. Importantly diagnostic capabilities for these absolute measurements are not human limited, but rather, are the consequential results of modulation transfer function (MTF) as demonstrated in FIG. 2. Using known isotope decay data as the absolute determination of changes in radiation count detection by nuclear cameras, their hardware and software, we demonstrated using sealed sources of Technetium 99-m (Tc-99m) that MTF is greater for a 64×64 matrix with a count reduction of 11% over fifty-five minutes for sestamibi isotope decay. The 128×128 matrix, while providing a more visually appealing picture for “qualitative” image comparison, was associated with an almost 50% loss of data, yielding inaccurate diagnostic results.